Allergic Contact Dermatitis from Luliconazole: Implication of the Dithioacetal Structure
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Letters to the Editor 271 Allergic Contact Dermatitis from Luliconazole: Implication of the Dithioacetal Structure Tomoko Tanaka, Takahiro Satoh and Hiroo Yokozeki Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Japan. E-mail: tntm.derm@ tmd.ac.jp Accepted September 26, 2006. Sir, causing the allergic reaction. Patch testing with a panel Allergic contact dermatitis caused by topically applied of anti-fungal agents revealed a positive reaction for agents is a problem that physicians seek to avoid during luliconazole and lanoconazole only (Fig. 1B, Table I). the treatment of skin diseases. In this report, we present Other ingredients of the luliconazole cream (dibutyl a case of allergic contact dermatitis caused by lulico- hydroxytoluene, stearic acid, cetostearyl alcohol, pro- nazole, an imidazole anti-fungal drug. Patch testing pylene glycol, benzyl alcohol, polysorbate 60, isopropyl suggested that luliconazole sensitivity might have been myristate, methyl p-hydroxybenzoate and petrolatum) attributable to its dithioacetal structure and revealed that had negative results on patch testing (data not shown). lanoconazole-sensitive individuals have a high risk of Because luliconazole and lanoconazole have a similar luliconazole sensitivity. chemical structure (Fig. 2), the patient was considered to have been sensitized with lanoconazole and to have cross-reacted with luliconazole, resulting in the allergic CASE REPORT contact dermatitis. A 65-year-old woman had been diagnosed with chromo- mycosis due to Phialophora verrucosa at the age of 14 DISCUSSION years. She had been treated with a variety of systemic anti-mycotic drugs, such as fluconazole, itraconazole, Luliconazole is a recently developed imidazole anti- amphotericin B and voriconazole. Her skin lesions had fungal agent. Although allergic contact dermatitis due partially improved, but complete remission could not to imidazole anti-fungal agents is not uncommon, be obtained. In addition to the systemic treatment, the no reports concerning luliconazole-induced contact patient was therefore started on a regimen of topical luli- dermatitis have been published. The patient presented conazole cream (Lulicon® cream 1%, Kayaku Co., Ltd). herein exhibited allergic reactions to both luliconazole Two days after starting luliconazole, itchy erythema and and lanoconazole. Patch testing with a panel of anti- papules appeared at the application site (Fig. 1A). fungal drugs revealed no cross-reaction with imidazole Patch testing showed a positive reaction to lulico- anti-fungal drugs that had a β-substituted 1-phenethyl nazole at 2 and 3 days after application. Since the pa- imidazole (β-SPI) structure, which is known to be one tient also reported a history of contact dermatitis from of the important determinants of imidazole-induced al- lanoconazole cream used for the treatment of tinea lergic contact dermatitis (1). In addition, it was unlikely pedis, we attempted to evaluate the antigenic epitope that a vinyl base was an antigenic determinant, as the Table I. Patch test results Drug tested Classification Day2 Day3 Luliconazole (1% pet.) vinyl imidazole ++ ++ Lanoconazole (10% pet.) vinyl imidazole ++ ++ (1% pet.) vinyl imidazole ++ ++ Neticonazole cream vinyl imidazole – – Ketoconazole cream β-SPI – – Miconazole cream β-SPI – – Sulconazole cream β-SPI – – Bifonazole cream other imidazole – – Clotrimazole cream other imidazole – – Butenafine cream benzylamine – – Terbinafine cream allylamine – – Liranaftate cream thiocarbamate – – Fig. 1. Clinical manifestations and cross-reactivity of luliconazole and Petrolatum – – – lanoconazole. (A) Severe erythema and small papules were observed around ulcerated nodules of chromomycosis on the forearm. (B) Patch testing with Patch tests were performed with Finn chambers and results were evaluated 1% luliconazole and 1% lanoconazole. Control patch testing with petrolatum according to ICDRG standards. Petrolatum was used as negative control. was negative. β-SPI: β-substituted 1-phenethyl imidazole. © 2006 Acta Dermato-Venereologica. ISSN 0001-5555 Acta Derm Venereol 86 DOI: 10.2340/00015555-0200 272 Letters to the Editor (4, 5), the present case suggests that the dithioacetal structure is essential for inducing contact dermatitis caused by luliconazole and/or lanoconazole. Hence, at least two major reasons for sensitivity to imidazole anti-fungal drugs should be recognized: β-SPI sensi- tivity and dithioacetal structure sensitivity, although a requirement of the vinyl base for the latter is uncertain. Luliconazole cream might frequently induce allergic contact dermatitis in individuals who are sensitive to lanoconazole cream, but not to neticonazole cream, due to the dithioacetal structure of the former drug. REFERENCES 1. Baes H. Contact sensitivity to miconazole with orth-chloro Fig. 2. Similarity in the chemical structure of the vinyl imidazole agents. cross-sensitivity to other imidazoles. Contact Dermatitis 1991; 24: 89–93. present patient did not cross-react with the vinyl imi- 2. Shono M. Allergic contact dermatitis from neticonazole hydrochloride. Contact Dermatitis 1997; 37: 136–137. dazole agent neticonazole (Fig. 2, Table I). Consistent 3. Umebayashi Y, Ito S. Allergic contact dermatitis due to with the present case, lanoconazole-sensitive patients both lanoconazole and neticonazole ointments. Contact have rarely cross-reacted with neticonazole in prior Dermatitis 2001; 44: 48–49. reports (2, 3). It was intriguing to note that luliconazole 4. Taniguchi S, Kono T. Allergic contact dermatitis due to and lanoconazole have the same dithioacetal chemical lanoconazole with no cross-reactivity to other imidazoles. Dermatology 1998; 196: 366. structure, which is not present in other imidazole agents 5. Tanaka N, Kawada A, Hiruma M, Tajima S, Ishibashi A. (Fig. 2). Although antigenic epitopes of lanoconazole- Contact dermatitis from lanoconazole. Contact Dermatitis induced contact dermatitis have not been well defined 1996; 35: 256–257. Acta Derm Venereol 86.